Ruthenium containing phthalocyanin photosensitizers

ABSTRACT

Water soluble salt or acid forms of a transition metal phthalocyanine of formula ##STR1## where M is a transition metal, X is H, alkyl, alkoxy, halide or X&#39;s together form --C 4  H 4  --, each R is a ligand with a solubilizing group, and Q is N or --CY-- where Y is H, alkyl, alkoxy or halide, are surprisingly active in tests indicating photodynamic properties. Novel compounds, preparative methods and pharmaceutical compositions are included.

This invention concerns photosensitizers, more particularly it concernsnovel transition metal photosensitizers.

BACKGROUND

In the photodynamic therapy of cancer, certain dye compounds (eg,hematoporphyrin derivative, chloroaluminum phthalocyanine sulfonate) areadministered to a tumor-bearing subject. To some extent these dyecompounds are taken up by the tumor tissue and upon selectiveirradiation with the appropriate light source the tumor tissue isdestroyed via the dye mediated photo-generation of toxic species such assingle; oxygen,

A large number of phthalocyanine (Pc) derivatives have been proposed aspotential photodynamic therapeutic (PDT) agents. Most biological studieson Pc compounds related to PDT have been conducted with water solublesulfonated metallo-phthalocyanines (as reported by Rosenthal. I.Photochem Photobiol 53(6). 859-870. (1991). These compounds aregenerally obtained by sulfonation of the appropriatemetallo-phthalocyanine or by template synthesis using the appropriatesulfonated precursors and a metal salt. Both template synthesis anddirect sulfonation results in mixtures of Pc's containing a variety ofisomers and/or different degrees of sulfonation. This is a particulardisadvantage with respect to pharmaceutical applications in that drugregulatory agencies are increasingly stringent in their requirements forsubstantially pure compounds.

Metallated Pc's have been found to have superior photosensitizingactivity compared to metal-free Pc's when the metal is a main groupelement having a filled d shell (eg. Al. Zn, Sn. In). It has beenreported by Chan, W S. et al. Photothem Photobiol. 45, 757-761 (1987),that transition metal complexes of Pc's have been found to be inactive(eg. Cu, Co, Ni. VO, Pal).

There remains a need for novel photosensitizers which can be prepared inisomerically pure form and which show a good level of activity.

The present invention provides novel transition metalphthalocyanine-type derivatives of formula I. ##STR2## wherein M is asecond or third row transition metal with a d⁶ low-spin electronicconfiguration,

X is hydrogen, alkyl, alkoxy, halide or adjacent X's may together form--C₄ H₄ --,

each R is a ligand selected from phosphine, mine, amine, isocyanide,nitrile, thiolate, hydrazine, cyanide, thiocyanate, phenolate, sulphideand analine groups having a water-solubilizing moiety, and

Q is nitrogen or --CY--, where Y is hydrogen, alkyl, alkoxy or halide,in water-soluble salt or acid form.

Preferably. M is selected from Ru, Rh, Os or Ir. Suitable ligands Rincorporate triphenylphosphine or triethylphosphine, and solubilizinggroups are suitably sulfonate or carboxylate groups. When R incorporatesan amine, it may be a straight or branched chain amine, or an aromaticamine such as pyridine. Preferred R ligands are triphenyl-phosphinemono-, di- or tri-sulfonate, 4-pyridine ethanesulfonate, 3-pyridinesulfonate, triphenylphosphine monocarboxylate, 4-isocyanobenzoate,nicotinic acid, taurine or amino acids.

Preferably, the compound is in salt form, with counterions which aredesirably K⁺, Na⁺ or quaternary ammonium.

The compounds of formula I are novel, and may be prepared by a processcomprising reacting a metal phthalocyanine compound of formula II,##STR3## wherein M, Q and X are as define above, and A is an amine,preferably a pyridine group, CO (carbon monoxide) or a co-ordinatingsolvent, for example benzonitrile, with a salt of the ligand R, andisolating the product compound of formula I.

Many of the reactants of formula II, and the salts of ligand R, areknown from the literature. However, compounds of formula II in which Ais ammine, benzonitrile, methylcyanide or another co-ordinating solvent,are believed to be novel and form part of the present invention.Although such compounds may be prepared by methods analogous to those inthe art, the invention further provides a method of producing said novelcompounds of formula II in which A is benzonitrile by reacting Mphthalocyanine bis(ammine) with benzonitrile. The ammine complex may beprepared by reacting MCl₃. xH₂ O, where x is 2 or 3, withphthalonitrile, and then with ammonia.

Suitably, the starting metal phthalocyanine or naphthalocyanine is mixedin an organic solvent, such as mixed xylenes, with an excess, forexample 2-10 fold stoichiometric, of an organic-soluble form of thewater solubilizing ligand, under an inert atmosphere, such as argon. Thereaction is carried out desirably by heating, for example at reflux forabout two days. The product may be isolated by the addition of aco-solvent to the reaction mixture. If required, the solubility of theproduct may be enhanced by exchanging the counterions, in generallyknown

It is believed that the present invention, by incorporating a watersolubilizing axial ligand, instead of the conventional substitution atthe periphery of the Pc to obtain water solubility, permits thesynthesis of isomerically pure compounds. The novel compounds have beenfound to be active in in vitro and in vivo tests for photosensitizingactivity described hereafter.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula I in admixture or association with apharmaceutically acceptable carrier or diluent. The invention is alsoconsidered to include a method of treatment of a mammal having a tumorsusceptible to photodynamic treatment, wherein the mammal isadministered an effective dose of a compound of formula I or apharmaceutically acceptable salt form thereof, and the tumor issubjected to light radiation.

The pharmaceutical compositions may be formulated according towell-known principles, and may desirably be in the form of unit dosagesdetermined in accordance with conventional pharmacological methods. Theunit dosage forms may provide a daily dosage of active compound in asingle dose or in a number of smaller doses- Dosage ranges may beestablished using conventional pharmacological methods and are expectedto lie in the range 1 to 50 mg/kg of body weight. Other active compoundsmay be used in the compositions or administered separately orsupplemental therapy may be included in a course of treatment for apatient. The pharmaceutical compositions may desirably be in the form ofsolutions or suspensions for injection, or in forms for topicalapplication, including application in the oral cavity. Suitable carriersand diluents are well known in the art, and the compositions may includeexcipients and other components to provide easier or more effectiveadministration.

Following administration to the patient, photodynamic therapy may becarried out in conventional manner, using light sources and deliverysystems that are known in the art. See, for example, Phys Med Biol.(1986). 31. 4. 327-360.

"BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates in vitro results obtained with a compound of theinvention in comparison to a prior art compound.

FIG. 2 graphically illustrates the depth of necrosis at varying dosagelevels for various compounds including a compound according to theinvention.

FIG. 3 illustrates the relationship of singlet oxygen production to thePC₅₀ of various compounds according to the invention in comparison witha prior compound."

The invention will now be illustrated by the following Examples, whichparticularly describe aspects of the invention but in no way limit itsscope.

The sodium salt of triphenylphosphine monosulfonate [Na(I)] and4-pyridine ethanesulfonic acid were obtained commercially, andRu(Pc)(pyridine)₂ was prepared by a literature method, (N P Farrell, etal. Inorg Chim Acta, 28, L144-L146. 1978).

EXAMPLE 1

K₂ [Ru(Pc)bis(triphenvlphosphine monosulfonate)]trihydrate (Compound A )

The tetrabutylammonium salt of triphenylphosphine monosulfonate [TBA(I)]was prepared by mixing 0.2 g of Na(I) and 0.23 g of tetrabutyl-ammoniumbisulfate [TBA(HSO₄)]in basic aqueous solution and extracting TBA(I)into methylene chloride. After washing the organic phase with water,solvent was removed to yield 0.34 g of TBA(I) as a yellow oil.

TBA(I) (0.34 g, 0.58 mmol) and Ru(Pc)(Py)₂ (0.15 g. 0.20 mmoI) wereadmixed in a mixed xylene solvent (10 ml) and the mixture heated toreflux for two days. At several times during the reaction period aportion of solvent was allowed to evaporate to remove pyridine andsufficient xylenes added to maintain the reaction volume at 10 ml. Uponcooling to room temperature, diethyl ether was added to precipitate ablue solid. This material was dissolved in a minimum volume of ethanoland filtered. To this solution was added potassium acetate (0.5 g) in 5ml of ethanol. The resulting crystalline blue solid was collected,washed with ethanol and diethyl ether and air dried. Yield =0.22 g. 78%based on Ru.

Analysis for C₆₈ H₅₀ K₂ N₈ P₂ O₉ RuS₂ Calc: C, 57.13; H. 3.53; N, 7.84Found: C, 57.13; H. 3.63; N, 8.05

EXAMPLE 2

K₂ [Ru(Pc)bis(4-pyridineethanesulfonate)]tetrahydrate

The tetrabutylammonium salt of 4-pyridine ethanesulfonate [TBA(II)]wasprepared by mixing TBA[HSO₄ ](6 g) and 3 g of the pyridine in water andadding 30% NaOH solution until the pH was greater than 11. This gave anoil which was subjected to rotary evaporation with a mixed xylenesolvent. The residue was dissolved in methylene chloride, filtered andextracted three times with water. Removal of solvent yielded a palegreen oil.

TBA(II) (0.72 g, 1.68 mmol) and Ru(Pc)(Py)₂ (0.14 g, 0.18 mmol) weredissolved in 25 ml of a mixed xylene solvent and the mixture heated toreflux under N₂ for two days, giving a near lorless solution. Thereaction was cooled to room temperature and the resulting blue solidcollected. Yield of [TBA]₂ [Ru(Pc) (4-pyridine ethanesulfonate)₂ ]=0,23g. This material was dissolved in ethanol (12 ml) and filtered. Additionof potassium acetate (0.35 g) in ethanol (3.5 ml) resulted in theprecipitation of a blue solid that was collected, washed with ethanoland diethyl ether and air dried. Yield =0.174 g, 87% based on Ru.

Analysis for C₄₆ H₄₀ K₂ N₁₀ O₁₀ RuS₂ Calc: C, 48.62; H. 3.55; N, 12.33Found: C, 48.46; H. 3.64: N. 12.06

EXAMPLE 3

Na₂ [Ru(Pc)bis(taurine)]hexahydrate

Taurine (0.28 g) and 0.20 ml of 10N NaOH in water were stirred in 10 mlof ethanol for 2 hours. RuPc(Benzonitrile)₂ (0.30 g) and 10 ml oftoluene were added and the resulting mixture was refluxed under nitrogenovernight. The solvents were removed and the residue washed with tolueneand methylene chloride. The remaining solid was dissolved in methanoland the solution filtered. The addition of toluene caused the product toprecipitate. The blue solid was collected, washed with methylenechloride and air dried. Yield =0.25 g (70%).

Analysis for C₃₆ H₄₀ N₁₀ Na₂ O₁₂ RuS₂ Calc: C, 42.56; H. 3.97; N, 13.79Found: C, 42.55; H. 3.85: N, 13.59

Many other compounds within the scope of the invention were preparedusing analogous methods to those of the above samples. The structuresare given in abbreviated form in the Table that follows the in vitrotesting section hereinafter. Most of the compounds are characterised bytheir light absorption maxime (λ_(max) Q) and molar extinctioncoefficients (εM⁻¹ cm⁻¹).

Starting Materials

Ruthenium phthalocyanine bis(ammine)

Ruthenium trichloride hydrate [RuCl₃. xH₂ O](2.32 g) was heated in 25 mlof pentanol until the solution had turned completely blue and all thewater had been distilled out. This solution was added over 3 minutes to6.5 g of phthalonitrile and 0.54 g of hydroquinone dissolved into 20 mlof boiling pentanol. The resulting orange suspension was refluxed for 3days under a slow purge of ammonia gas. The reaction was cooled to roomtemperature and the purple solid filtered off. The solid was washed withmethanol and methylene chloride, repeatedly, until the washings werenearly colourless. The solid was air dried. The yield of 6.58 g ofRuPc(NH₃)₂ was used without further purification.

Ruthenium phthalocyanine bis(benzonitrile)monohydrate

The RuPc(NH₃)₂ was refluxed in 75 ml of PhCN for one day under nitrogen.The mixture was diluted to 1 litre with hot chloroform and stirred atreflux for one hour. The solution was filtered hot and 31 of methanolwas added to the filtrate. A first crop of product, 5.39 g filtered offafter 16 hours. A second crop was isolated by reducing the filtrate to2.51 by boiling. This gave an additional 1.48 g of product. The totalyield was 6.87 g. 84%, of purple crystals.

Analysis for C₄₆ H₂₈ N₁₀ ORu Cale: C, 65.9; H. 3.37; N. 16.72 Found: C,65.58; H. 3.33; N. 16.78

Photochemical and Biological Studies

Singlet Oxygen Generation

Singlet oxygen generation was determined by the photo-degradation ofnitrosoanaline dye following the method of Kraljic and Mohsni (PhotochemPhotoBiol, 28. 577-581 (1978). A stock buffer of oxygen saturated 50 mMNa phosphate pH =7.5. 16 mM imidazole (recrystallized from benzene) wasmixed 1:1 with the test compound in water and 2.5 μl/ml ofN,N-dimethyl-p-nitrosoanaline was added in the dark.

100 μl of the test solution was plated out in triplicate on a Coming 96well plate and exposed to light from a Kodak slide projector with anunfiltered 300W 82 U FHS incandescent lamp, producing black bodyradiation at 1700 K. at a distance of 35 cm from the plate, which ismaintained at 4° C. in a cold box for 15 minutes of irradiation.

Decomposition of the nitroso dye is followed at 450 nm with a DynatechMR600 microplate reader (test λ450 nm, ref λ540 nm).

FIG. 3 attached shows the relationship of singlet oxygen production tothe PC₅₀ of various ruthenium phthalocyanine compounds according to theinvention and aluminjure phthalocyanine sulphonate. In the Figure theabbreviations for the ligands are used to represent the entire molecule.eg RuPc(TPPMS)₂ =TPPMS. A full list of abbreviations is given below.

The compounds described produce singlet oxygen at a rate which variesten-fold with respect to molar sensitizer concentration. However, thereis no correlation of the rate of singlet oxygen production and theeffectiveness of the compounds as measured by the PC₅₀ values for thecompounds. The rate of singlet oxygen production of aluminiumphthalocyanine sulphonate is on the order of one or two logs better thansome of the sensitizers listed yet the effectiveness of many of thesecompounds described are higher than the aluminium compound. Thissuggests improved uptake of these compounds or a novel site of actionwithin the cells.

Phototoxicity (Light)

Phototoxicity experiments follow the procedure used by Glassberg et al.(Glassberg. E. Lewandowski. L. Lask. G and Vitto.J, J Invest Dermatol.94. 604-610 (1990). Adherent cells (HeLa RCA. SKOV OVCAR) are plated at4×10⁴ cells/well in a 94 well Coming microtiter plate in RPMI 1640 andFCS for four hours. The sensitizer is added in the same media at a setconcenuation range in triplicate, and the cells are incubated for 24hours at 37° C. with 5% CO₂.

The media is removed and the cells washed three times with D-PBS. andthen covered with D-PBS (200 μl ) and exposed to light from the samesource used in the singlet oxygen assay. Irradiation time can be variedbetween one and fifteen minutes, at which time the D-PBS is removed andfresh media RPMI-1640 +FCS is added and the cells incubated as beforefor sixteen hours.

³ H-thymidine (50 μl ) in RPMI-1640 +FCS is added and the cells areincubated for a further four hours, at which time they are harvested onglass filter mats and the incorporation of 3H-thymidine is determinedrelative to an untreated (no sensitizer added) control.

Cytotoxicity

This follows the procedure for phototoxicity except that the cells arenever exposed to light. The assay is relative to a non-treated control.

Results

The in vitro results obtained with Compound A. K₂ [RuPc(TPPMS)₂ ], areshown in comparison to chloroaluminum phthalocyanine suffonate obtainedfrom Porphyrin Products. Logan. Utah. in FIG. 1 of the attacheddrawings.

Compounds according to the invention were assessed and characterised bytheir light absorption maxima, and their molar extinction coefficientsaccording to conventional test procedures. Most of the compound weretested for their biological activity according to conventional testprocedures in the art. The PC₅₀ represents phototoxic concentration 50%.which is the concentration of compound when exposed to a light dose asdescribed herein, causes a 50% reduction in cancer cell growth vs anuntreated control population. The phototoxicity index. PI, is the ratioof the PC₅₀ to the cytotoxic concentration 50%. where the growth isreduced by 50% without a light dose being given.

The results are listed in the Table below: the abbreviations used toidentify the compounds are given after the Table. PC₅₀ is determined bya relatively simple in vitro assay on a cellular level, which isgenerally indicative of photosensitizing activity. However, since somephotosensitizers function on a tissue/organ level, inactivity in thePC₅₀ assay as shown by certain compounds below does not determine thatthe compounds are not active.

    __________________________________________________________________________    Compound    λ.sub.max Q                       ε M.sup.-1 cm.sup.-1                              PC.sub.50                                     PI    __________________________________________________________________________    RuPc(TPPTS).sub.2                650 W  8.74 × 10.sup.4                              1.13 × 10.sup.5                                     >15    RuPc(TPPMS).sub.2 (Ex 1)                650 W  8.82 × 10.sup.4                              1.14 × 10.sup.-6                                     >100    RuPc(TPPMS).sub.2                652 W  9.03 × 10.sup.4    RuPc(3PS).sub.2                630 W  7.36 × 10.sup.5                              9.29 × 10.sup.-7                                     >109    RuPc(Nic).sub.2                630 W  6.48 × 10.sup.5                              1.26 × 10.sup.-6                                     >79    RuPc(Tau).sub.2 (Ex 3)                623 M/634 W                       7.98 × 10.sup.4                                9 × 10.sup.-6                                     >1.1    RuPc(5AS).sub.2                635 W  6.65 × 10.sup.4                                2 × 10.sup.-6                                     >10    RuPc(TAC).sub.2                633 W  3.11 × 10.sup.4                              8.6 × 10.sup.-7                                     2.9    RuPc(ABA).sub.2                638 W  7.25 × 10.sup.4                              3.5 × 10.sup.-6                                     8.8    RuPc(ATS).sub.2                636 W  7.48 × 10.sup.4                              2.27 × 10.sup.-6                                     >4.4    RuPc(CBA).sub.2                650 W  9.76 × 10.sup.4                              4.2 × 10.sup.-7                                     10.2    Ru(oMe).sub.8 Pc(35PDCA.sub.2)                641 W  6.33 × 10.sup.4                              Inactive                                     1    RuPc(ASP).sub.2                635 W  8.99 × 10.sup.4                              2.6 × 10.sup.-5                                     >3.8    RuPc(ARG).sub.2                635 W  1.03 × 10.sup.5                              1.8 × 10.sup.-5                                     1.3    RuF.sub.16 Pc(Nic).sub.2                635 W  5.57 × 10.sup.4                              Inactive                                     1    RuPc(β-ALA).sub.2                635 W  1.05 × 10.sup.5                              1.9 × 10.sup.-6                                     26.3    RuPc(34PDCA).sub.2                630 W  5.88 × 10.sup.4                              2.1 × 10.sup.-6                                     47.6    RuPc(35PDCA).sub.2                632 W  4.84 × 10.sup.4                              1.8 × 10.sup.-5                                     >5.6    RuPc(PMP).sub.2                na     na     5.8 × 10.sup.-7                                     25.8    RuNc(TPPTS) 650 W  na       3 × 10.sup.-5                                     3    RuNc(TPPTS).sub.2                720 W  na      >1 × 10.sup.-4                                     na    RuNc(TPPMS).sub.2                734 W   5.4 × 10.sup.4                              2.7 × 10.sup.-6                                     1.6    RuNc(Nic).sub.2                762 W  1.69 × 10.sup.5                              1.05 × 10.sup.-7                                     22.2    RupyrPc(Nic).sub.2                625 W  4.51 × 10.sup.4                              Inactive                                     1    RuPc(py)(TPPMC)                644 W  5.46 × 10.sup.4                              na     na    Ru(TPPMC).sub.2                na     na     1.5 × 10.sup.-6                                     20    RuNc(β-ALA).sub.2                730 W  3.65 × 10.sup.4                              9.6 × 10.sup.-7                                     1.51    RuNc(3PS).sub.2                730 W   8.3 × 10.sup.4                              4.6 × 10.sup.-7                                     32.6    RuPc(PES).sub.2 (Ex 2)                632 W  7.25 × 10.sup.4                              Inactive                                     1    __________________________________________________________________________

    ______________________________________    Abbreviations    ______________________________________    Core Structures    RuPc      Ruthenium(II)phthalocyanine    Ru(oMe).sub.8 Pc              Ruthenium(II)-2,3,9,10,16,17,23,24-octamethyl-              phthalocyanine    RuNc      Ruthenium(II)naphthalocyanine    RuF.sub.16 Pc              Ruthenium(II)-1,2,3,4,8,9,10,11,15,16,17,18,22,23,-              24,25-hexadeca-fluorophthalocyanine    RupyrPc   Ruthenium(II)-1,4,8,11,15,18,22,25-octaaza-              phthalo-cyanine    Ru(pMeO).sub.8 Pc              Ruthenium(II)-1,4,8,11,15,18,22,25-octamethoxy-              phthalocyanine    Axial Ligands    TPPTS     Sodium triphenylphosphine-m-trisulfonate    TPPMS     Potassium triphenylphosphine-m-sulfonate    TPPMC     Sodium triphenylphosphine-m-carboxylate    3PS       Sodium 3-pyridinesulfonate    Nic       Nicotinic acid    PMP       Sodium 3-pyridinemethylphosphate    34PDCA    3,4-pyridinedicarboxylic acid    35PDCA    3,5-pyridinedicarboxylic acid    Tau       Sodium 2-aminoethanesulfonate (Taurine)    5AS       5-aminosalicylic acid    TAC       Potassium thio-acetate    ABA       3-aminobenzoic acid    ATS       Potassium 4-amino-2-toluenesulfonate    CBA       3-cyanobenzoic acid    ASP       Potassium aspartate    ARG       Arginine    β-ALA              β-Alanine, Potassium salt    PES       Potassium 4-pyridine ethanesulfonate    Miscellaneous    W         Water    M         Methanol    i         Insoluble    DW        Decomposes in Water    na        not analyzed    ______________________________________

In Vivo Studies

The photodynamic threshold dose in normal rat liver was used as a model.This has been developed by Singh and Wilson at McMaster University andused to study both chloroaluminum phthalocyanine sulfonate (ASPc) andphotofrin (Patterson, M S, et at, Photochern Photobiol, 51,343-349,1990, and Farrell, T J, et at, Proc SPIE1426, 146-155, 1991).

Procedure

1. Inject compound at 2.5 mg/ml into tail vein of adult Wistat rats atdoses of 5, 10.20 mg/kg.

2. 24 hours later expose liver by laparotomy and irradiate surface at upto four locations with a 5 mm diameter lightbeam from an argon-dye laseroperating at 650 nm: incident power =40 m Watt: incident fluenee rate=200 mW cm⁻² : treatment time =5 or 10 minutes (60. 120 Joules cm⁻²).

3. 24 hours later inject Evans Blue iv, sacrifice at 15 minutes, sectionLiver through each radiation spot and measure depth of necrosis asindicated by dye exclusion.

Results

The measured depths of necrosis are given in Table 1 below and shown inFIG. 2 together with the most comparable data for AISPc and Photofrin(which were administered ip not iv). Compound A is clearly shown to bephotodynamically active in vivo. The depths of necrosis at similar drugand light levels are comparable to those with previously studied agents,including the current clinical photosensitizer. Photofrin.

                  TABLE 1    ______________________________________    Injected        Incident Depth of    Dose            Fluence  Necrosis    Compound A      (J cm.sup.-2)                             (mm)    ______________________________________     0              60, 120  0*     5               60      1.86 ± 0.34     5              120      2.5 ± 0.0    10               60      2.16 ± 0.10    10              120      2.41 ± 0.16    20               60      1.66 ± 0.05    20              120      1.94 ± 0.04    ______________________________________     *No-drug control is established in previous studies, and produced no     measurable necrosis at these fluence rates and fluences.     ± Standard Deviation based on two irradiation spots in each of two in     each of two animals per data point.

We claim:
 1. A compound which is a transition metal phthalocyanine ornaphthalocyanine derivative of formula I ##STR4## wherein M is Ru X ishydrogen, alkyl, alkoxy, halide or adjacent X's may together form --C₄H--₄,each R is a ligand selected from phosphine, arsine, amine,isocyanide, nitrile, thiolate, hydrazine, cyanide, thiocyanate,phenolate, sulphide and aniline groups having a water-solubilizingmoiety, and Q is nitrogen or --CY--, where Y is hydrogen, alkyl, alkoxyor halide, in water-soluble salt or acid form.
 2. A compound accordingto claim 1, wherein R is selected from the group consisting oftriphenylphosphine, triethylphosphine and amine having one or moresulfonate or carboxylate groups.
 3. A compound according to claim 2,wherein R is selected from the group consisting of triphenylphosphineand pyridine having one or more sulfonate or carboxylate groups.
 4. Acompound according to any one of the preceding claims, wherein thephthalocyanine structure is substituted by eight methyl or methoxygroups.
 5. A compound according to claim 1, which isZ₂[Ru(Pc)bis(triphenylphosphine monosulfonate)] wherein Z is a counterion.6. A pharmaceutical composition comprising a compound of formula Iaccording to claim 1, in admixture or association with apharmaceutically acceptable carrier or diluent.
 7. In the photodynamictherapy of cancer wherein a dye compound is administered to atumor-bearing subject, the improvement which comprises using, as the dyecompound, a compound according to claim 1.